Diabetes is the most frequent metabolic disease. In 2010 about 285 million people suffered from diabetes worldwide, with a steadily increasing incidence. It has been estimated that in 2030 about 439 million people will suffer from diabetes worldwide. In Germany, about 6 to 7 million people live with diabetes, 90-95% with type 2 diabetes.
Diabetes mellitus is the most expensive chronic disorder, causing costs of about 25 billion Euros in Germany in 2005. The costs have been steadily increasing and were about 40 billion Euros in 2010. More than ¾ of these costs are associated with the treatment of subsequent disorders; chronic hyperglycemia is deemed to be an independent risk factor for vessel complications and might cause retinopathy, myocardial infarct, apoplexia, neuropathy, nephropathy and even renal failure.
Type 2 diabetes is characterized by a defective insulin release in response to glucose, a defective response to insulin by liver, fat and muscle cells, enhanced glucose blood levels, reduced glucose tolerance, enhanced insulin blood levels, enhanced triglycerides and enhanced fat tissue. Inflammatory cytokines are enhanced in diabetes patients. Overweight is one of main key predictors for diabetes type 2 and a good correlation between obesity and abnormal glucose tolerance is described in several studies. A defective insulin release in response to glucose is a major defect in type 2 diabetes.
Therapy of type 2 diabetes aims at reducing the chronically increased glucose level in the blood as well as improving the existing insulin resistance.
Oral antidiabetic drugs that have been currently available so far are problematic and not satisfactory in every respect.
Glucose levels in blood can be effectively decreased by administration of sulfonylureas and insulin. However, such treatment is associated with a high risk of hypoglycemia, having the consequence of ambulant or stationary treatment, particularly in the elderly. Three or more severe hypoglycemias in patients suffering from type 2 diabetes have been found to substantially increase the risk of developing dementia. In addition, sulfonylureas are associated with an increased risk of mortality, in particular when combined with metformin.
DDP-4 inhibitors have a low risk of hypoglycemia, but merely lead to a slight improvement of the HbA1c-value compared to metformin. Further, there is no long-term evidence as to tolerability, mortality and diabetes complications.
Most long-term experiences are available for metformin, an extensively administered antidiabetic drug. It is particularly effective in overweight diabetics and reduces diabetes complications and mortality by about 30%. However, monotherapy is typically effective only in the beginning of the treatment; in view of deteriorating function of beta cells and decrease of insulin segregation a second oral antidiabetic drug, typically sulfonylureas, or insulin, must usually be administered in the course of long term treatment.
Currently available diabetes medications cannot suppress or at least decelerate progressive destruction of beta cells.
Morphinan-derivatives have been known as medicaments for many years. The compounds have shown only minor adverse events upon long term administration and thus, are generally well tolerated.
D. Konrad et al., Diabetologia 2000, 43(2):261-2 report that high-dose dextromethorphan in children with severe bacterial meningitis unexpectedly caused the development of type I (insulin dependent) diabetes mellitus as serious adverse event. The study reports on two children suffering from severe bacterial meningitis who developed an insulin dependent diabetes mellitus while taking 36 mg kg−1 day−1 dextromethorphan. It has to be mentioned that these patients received intensive care treatment besides glucocorticoids, which are known to induce a diabetic metabolic state. Importantly, the diabetes completely disappeared after the treatment for bacterial meningitis was stopped. Since these two bacterial meningitis patients do not represent the population of type I or type II diabetic patients, the reference has no relevance as to the usefulness of dextromethorphan in the treatment of diabetes.
K. A. Nelson et al., Neurology, 48(5), 1997, 1212-8 discloses that dextromethorphan is effective in treating painful diabetic neuropathy.
H. Monyer et al., Brain Research, 446(1), 1988, 144-8 discloses that morphinans attenuate neuronal injury induced by glucose deprivation.
E. S. Tecome at al., Neuron, 2(6), 1989, 1541-5 reports that dextrorphan is a neuroprotective agent useful against neuronal injury.
WO 2008/137474 discloses compounds that are said to be useful for treating diabetic neuropathy, neurological diseases, brain injury and neuropathic pain.
J. R. Hadcock et al., Drug Discovery Today: Therapeutic Strategies, 2(2), 2005, 171-5 discloses that butorphanol and other opioid agonists are orexigenic in humans, while opioid antagonists are antiorexigenic.
A. Goldstein et al., Proc. Natl. Acad. Sci. USA 1990, 1629-32 discloses dextrorphane as a μ receptor antagonist.
L. Barclay, 2003, XP55012440, Internet discloses levorphanol, the enantiomer of dextrorphan, is a μ receptor agonist useful in treating neuropathic pain.
WO 02/13759 discloses μ agonists, such as levorphanol, for use in the treatment of diabetes type 2.
There is a demand for alternative treatments of diabetes and related disorders that overcome the drawback of the prior art. It is therefore an object of the invention to provide medicaments that are useful for the treatment of diseases or conditions selected from insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, obesity, neuropathy and/or nephropathy that have advantages compared to the prior art.
This object has been achieved by the subject-matter of the patent claims.